Cancer treatment goes viral...

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Behind the Headlines

Thursday June 14 2012

Researchers aim to fight cancer with some common viruses

“A bug that normally gives children the sniffles could fight cancer,” the Daily Mail has reported. The newspaper says that a “cancer-zapping drug based on the virus could be in widespread use in as little as three years”.

The news is based on research looked at whether a virus, which has previously been demonstrated to have cancer-fighting properties (reovirus), could be injected into the bloodstream and reach cancer cells without first being destroyed by the body’s immune cells. The study was not designed to examine whether the virus was capable of fighting cancer.

The study involved 10 patients with bowel cancer who were scheduled for surgery to remove cancer that had spread to their livers. The patients were injected with reovirus and then assessed to see how much of the virus remained in various tissues and cell samples. They found that the virus had made its way into certain blood cells, where it went unnoticed by the immune system. After surgery, researchers found that the virus had then successfully entered liver cancer cells, but had not targeted healthy cells, indicating that it may have potential as a cancer therapy.

This small, early-stage study was set up to discover whether the virus could slip past the immune system and reach cancerous cells, but did not investigate whether it went on to destroy cancer cells. It therefore presents initial tests of an exciting new technology, but cannot confirm whether it can be used as an effective treatment for cancer.

Where did the story come from?

The study was carried out by researchers from the St. James’s University Hospital in Leeds, the universities of Leeds and Surrey, and other institutions throughout the UK, Canada and the US. The research was funded by Cancer Research UK, the Leeds Experimental Cancer Medicine Centre, the Leeds Cancer Research UK Centre, the Leeds Cancer Vaccine Appeal and the Rays of Hope Appeal.

The study was published in the peer-reviewed medical journal Science Translation Medicine.

The research was generally covered appropriately by the media. The BBC provided a clear description of the technology and research, and highlighted that the precise mechanism through which the virus infects cancer cells is not yet understood. However, although this was a study in cancer patients, media estimates that the virus could be used as a clinical treatment within three years are quite optimistic, and should be treated with caution.

What kind of research was this?

When a virus infects us, it replicates its genetic material within our healthy cells, effectively taking over the cell. In the same way certain viruses have been shown to target cancerous cells and therefore may have cancer-fighting properties. These viruses are able to invade cancer cells, replicate once inside and then burst the cell, which in turn triggers the body to mount an immune response against the tumours.

Previous studies have suggested that the best way to get cancer-fighting viruses into cancer cells is by directly injecting the virus into the tumour. This has been considered a major limitation of the approach, as it would only work for easily accessible and identifiable tumours. Researchers were therefore interested in developing a method to allow the virus to access cancer cells throughout the body, ideally by injecting it into the bloodstream. To be viable as a potential treatment using this method, viruses need to be able to evade detection and destruction by the patient’s immune system, allowing them to reach and invade the cancer cells.

This was an experiment in 10 patients with bowel cancer. Such small-scale studies are often used as a means to prove that an underlying scientific concept is valid in human patients. These studies generally follow similar studies in animals, and allow researchers to ensure that a new technology or therapy is safe for humans. When such proof-of-concept studies are successful, they provide justification for larger-scale studies to assess how safe and effective the potential therapy is.

While such studies are a valuable and necessary step in the drug development process, the conclusions we can draw from them are quite limited. They can show that the theory underlying the process is valid, but they cannot tell us how effective the therapy is at treating the disease. In order to evaluate this, larger controlled clinical trials are needed.

What did the research involve?

The researchers recruited 10 patients with advanced bowel cancer that had spread to the liver. All of the patients were scheduled to have the liver tumours removed surgically. The researchers took a blood sample and determined whether the patients had a specific ‘antibody’ that can detect and attach to reovirus. Antibodies are special proteins used by the body to help it detect specific threats such as bacteria and viruses it has encountered in the past. Essentially they flag them up so that in future the body knows there is a foreign threat that needs to be destroyed by the immune system, reducing the time the body will take to respond.

The researchers then injected each of the patients with the reovirus between six and 28 days before their surgery. They took a series of blood samples, and tissue samples of the cancerous and healthy liver tissues. They examined these samples to determine which cells the virus could be found in, and to see whether or not it was identified and destroyed by the immune system before reaching the cancer cells.

Given the early, exploratory nature of the study, it focused on how effectively the technique delivered the virus to cancer cells, not on its effectiveness as a cancer therapy. The researchers examined whether or not the virus could successfully navigate the body to arrive at and infect the cancerous cells. It did not assess the effectiveness of the virus at bursting the cancer cells, triggering an immune response against the tumours, or shrinking the tumours.

What were the basic results?

The researchers found that all 10 patients had the antibodies needed to detect reovirus present in their bloodstream at the start of the trial. This is important because the presence of antibodies ensured that the lack of an immune response was due to the virus’s ability to avoid detection, not due to the body not recognising reovirus as a potential threat. They found that the levels of reovirus antibodies increased throughout the trial, peaking just before surgery.

The researchers then measured the amount of virus in various tissues and cells:

Plasma: the virus was present in the plasma, the liquid portion of blood that surrounds the blood cells, immediately after the injection. However, these levels dropped over time.

Blood mononuclear cells (PBMCs): the virus had attached to the PBMCs (which is a type of white blood cell) within an hour of injection in some of the patients. Unlike the virus levels found in the plasma cells, the amount of virus in PBMCs increased over time in two patients, This indicates that the reovirus attached to (or ‘hitchhiked’ with) these particular cells, which may allow it to avoid detection and destruction by the patients’ immune systems.

Liver tumour cells: reovirus was found in nine of the 10 patient’s tumour tissue samples. This indicates that the virus was able to reach and infect the cells without being detected by the patients’ immune systems. The researchers also found evidence that once inside the cell, the virus was able to replicate itself - an essential step if reovirus is to be considered for therapeutic purposes.

Healthy liver cells: reovirus was detected in five of the patient’s healthy liver cells at lower levels than in the liver tumour cells, and was not present in the healthy liver cells of the remaining five patients. This indicates that the virus can specifically target the cancerous cells for infection in some patients, although not all.

How did the researchers interpret the results?

The researchers conclude that reovirus was able to avoid detection by the immune system and infect cancer cells.

Conclusion

This small, early, development-stage study aimed to see whether a cancer-fighting virus could be injected into the bloodstream and successfully infect cancerous liver cells, without first being destroyed by the body’s immune system. The findings suggest that a particular virus, reovirus, is able to evade the body’s immune system by attaching to a particular type of blood cell. Such evasion is necessary if the virus is to be used as an anti-cancer therapy that is delivered through the blood. The study did not aim to assess the effectiveness of the virus at bursting the cancer cells, triggering an immune response against the tumours, or shrinking the tumours.

Whether it comes to chemotherapy, radiotherapy or the use of viruses, there is an ongoing drive to create cancer therapies that specifically target tumours and cancerous cells. This is in a bid to both ensure that treatments effectively attack cancer cells and to limit the detrimental effects they have on healthy tissue. While past research has looked at injecting viruses directly into tumours, this new study has looked at using the bloodstream as a delivery system. This could potentially have the advantage of being able to spread a therapeutic virus into inaccessible cancer cells.

This trial provides an interesting proof-of-concept study, although it does not have immediate clinical significance: a great deal of additional research will be needed in order to determine whether reovirus is a safe treatment for patients, and whether it has any effect at destroying cancer cells. Based on the exploratory results of this study it is unknown at this stage precisely what types of cancer may be targeted by the virus, and which patients may respond to such therapy.

The 10 patients included in this study did not all have the same levels of virus in their blood and tissues. Further large-scale studies will be needed to determine whether patients consistently take up the virus in the same way, and, if so, whether or not there are particular characteristics that make this response more likely.

The researchers say that reovirus is currently being tested in Phase III clinical trials, the last stage of drug development trials. Estimates that the virus could be used as a cancer therapy within three years are perhaps a little speculative: while clinical trials in patients with cancer have begun, the drug development process is complicated, and many therapies do not successfully complete the process. The suggestion that reovirus could be offered as a cancer therapy by 2015 is an optimistic estimate, and we will need to watch how this research develops before drawing any conclusions about its eventual use in fighting cancer.